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Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation

Journal article
Authors Petra Bergström
Lotta Agholme
Faisal Hayat Nazir
Tugce Munise Satir
J. Toombs
H. Wellington
Joakim Strandberg
Thomas Olsson Bontell
Hlin Kvartsberg
Maria Holmström
Cecilia Boreström
Stina Simonsson
T. Kunath
Anders Lindahl
Kaj Blennow
Eric Hanse
Erik Portelius
S. Wray
Henrik Zetterberg
Published in Scientific Reports
Volume 6
Pages 29200
ISSN 2045-2322
Publication year 2016
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 29200
Language en
Links dx.doi.org/10.1038/srep29200
Keywords pluripotent stem-cells, cerebral-cortex development, alzheimers-disease, cerebrospinal-fluid, secretase cleavage, in-vivo, peptides, mutation, domain, bace, Science & Technology - Other Topics
Subject categories Neurology

Abstract

Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by A beta 1-40/42, is associated with mature neuronal phenotypes.

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